Various glucarolactone-based compounds, including calcium glucarate (CGT), micro-encapsulated D-glucaro-1,4-lactone, potassium hydrogen glucarate and 2,4-di-O-acetyl-D-glucaro-1,4-lactone, are known to be effective as inhibitors of .beta.-glucuronidase in cells, blood, urine and in the intestine and liver. By inhibiting .beta.-glucuronidase, less detoxified (that is glucuronidated) toxins are hydrolysed and therefore more toxins are excreted. As a result, such glucarolactone-based compounds are useful in the treatment and prevention of various types of cancer. See, for example, Walaszek, Z. et al. Inhibition of 7,12-dimethylbenzanthracene-induced rat mammary tumorigenesis by 2,5-di-O-acetyl-D-glucaro-1,4:6,3-dilactone, an in-vivo .beta.-glucuronidase inhibitor. Carcinogenesis 5: 767-772, (1984); Walaszek, Z., et al., Dietary glucarate-mediated reduction of sensitivity of murine strains to chemical carcinogenesis. Cancer Letters 33: 25-32, (1986); Walaszek, Z. et al., Dietary glucarate as anti-promoter of 7,12-dimethyl-benzanthracene-induced mammary tumorigenesis. Carcinogenesis 7: 1463-1466, (1986); and, Walaszek, Z., et al., Inhibition of N-methyl-N-nitrosourea--induced mammary tumorigenesis in the rat by a .beta.-glucuronidase inhibitor. IRCS Medical Science 14: 677-678, (1986).
Retinoid-based compounds including retinylacetate, retinylmethyl ether, 13-cis-retinoic acid and N-(4-hydroxyphenyl) retinamide (HPR), have similarly been investigated for their anticarcinogenic acitivity. See for example, Abou-Issa, H., et al., Anti-carcinogenic effect of retinoids on 7,12-dimethylbenz(a) anthracene-induced mammary tumor formation and its relation to cyclic AMP-dependent kinase. Biochem. Biophys. Res. Commun. 135: 116-123, (1986); Welsch, C. W., et al., Retinoids and Mammary gland tumorigenesis in Diet, Nutrition and Cancer (B. S. Reddy and L. A. Cohen eds.) CRS Press Boca Raton, FL. pp 1-21, (1986); Schamberger, R. J., Chemoprevention of cancer in Diet, Nutrition and Cancer. (B. S. Reddy and L. A. Cohen eds.) CRC Press, pp. 43-62, (1986); and, Moon, R. C., Inhibition of 7,12-dimethylbenzanthracene-induced mammary carcinogenesis by retinyl acetate. Cancer Res. 36: 2626, (1976).
These studies confirmed the activity of relatively high doses of retinoids against the chemical induction of mammary carcinogenesis in the rat. Similarly, high dosages were tested against the chemical carcinogen-mediated induction of tumors in the mammary gland, lung, skin, intestine and liver. Further, retinoids have been shown to protect skin, nasopharnyx, lower respiratory tract, urinary bladder and colon against carcinogens. In addition, these retinoic acid analogs (Vitamin A active compounds) have been tested in combination with the micronutrient selenium.
One problem associated with the use of retinoid-based compounds is that relatively high doses of the retinoids must be administered in order to achieve the desired anticarcinogen effect. Such high doses of retinoids often results in cummulative toxicity, with the excess retinoids being deposited in the liver.
However, there has been no suggestion in the art that a combination of glucarolactone-based compounds and retinoid-based compounds would be especially useful as anticarcinogens; that is, that the combination of these compounds would represent an alternative for use in the prevention of cancer or for use in the therapeutic treatment of cancer.
It has now been found that the use of a combination of glucarolactone-based compounds and retinoid-based compounds or their pharmaceutically-acceptable salts and esters, compounds which are known to be safely administered to humans and animals, significantly reduce the incidence of tumors and further prevent the formation of cancer.
It is therefore an object of the present invention to provide a safe and effective method for inhibiting the formation of tumors and for reducing the incidence of cancer in certain high risk populations.